Project Summary Solid organ transplantation is a lifesaving treatment for patients with end-stage organ failure, but long- term allograft survival is limited by immune rejection and side effects of immunosuppressive drugs. Allogeneic T cell responses are central to transplant outcomes (rejection versus tolerance). It is thus essential to define the T cell effector programs that affect the transplant outcomes. We recently discovered that interferon regulatory factor 4 (IRF4) is a key transcriptional determinant controlling allogenic T cell response in transplantation. IRF4 deletion in T cells results in progressive establishment of CD4+ T cell dysfunction and long-term cardiac allograft survival. These findings have been accepted for publication in Immunity. Herein, we hypothesized that IRF4 governs transplant outcomes through controlling the core regulatory circuits of T cell function. Therefore, the central focus of this proposal is to identify the IRF4 controlled regulatory circuits in alloreactive effector T cells.